The following information is obtained from various newswires,
published medical journal articles, and medical conference presentations.
Company: Cephalon
Approval Status: Approved March 2008
Treatment for: chronic lymphocytic leukemia
General Information
Treanda contains bendamustine hydrochloride, an alkylating drug, as the active ingredient. Bendamustine is a bifunctional mechlorethamine derivative. Mechlorethamine and its derivatives dissociate into electrophilic alkyl groups. These groups form covalent bonds with electron-rich nucleophilic moieties. The bifunctional covalent linkage can lead to cell death via several pathways.
Treanda for Injection is specifically indicated for the treatment of chronic lymphocytic leukemia.
Treanda is supplied as a single-use vial containing 100 mg of bendamustine HCl powder designed for intravenous administration. The recommended initial dose of the drug is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles.
Treanda administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant > Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered, Treanda can be reinitiated at the discretion of the treating physician.
Dose modifications for hematologic toxicity
For Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle.
Dose modifications for non-hematologic toxicity
For clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle.
Clinical Results
FDA Approval
The FDA approval of Treanda was based on the results of an open-label, randomized, controlled multicenter trial. This study enrolled 301 previously-untreated patients with Binet Stage B or C (Rai Stages I - IV) CLL requiring treatment. The subjects werr randomly assigned to receive either Treanda at 100 mg/m2, administered intravenously over a period of 30 minutes on Days 1 and 2 or chlorambucil at 0.8 mg/kg (Broca’s normal weight) administered orally on Days 1 and 15 of each 28-day cycle. The efficacy endpoints were objective response rate and progression-free survival. The overall response rate in the Treanda group was 90% versus 38% in the chlorambucil arm (p<0.0001). There was a 13% complete response rate, 4% Nodular partial response rate and 73% partial response rate in the Treanda arm compared to 1% complete response, 0% Nodular partial response and 37% partial response rate. The median progression free survival rate in the Treanda arm was 18 months versus 6 months in the chlorambucil arm.
Ongoing Study Commitments
- Cephalon has agreed to provide an updated study report of Protocol 02CLLIII titled "Phase III, Open-Label, Randomized, Multicenter Efficacy and Safety Study of Bendamustine Hydrochloride Versus Chlorambucil in Treatment-Naive Patients with (Binet Stage B/C) BCLL Requiring Therapy" at data cut off date in May 2008. Response rate, progression-free survival, overall survival and safety updates will be provided in this study report.
Protocol Submission: N/A
Study Start: N/A
Final Report Submission: February, 2009 - Cephalon has agreed to submit the results and data from the ADME Study 1039 titled "An Open-Label Study to Investigate the Pharmacokinetics (Distribution, Metabolism, and Excretion) of Bendamustine Hydrochloride Following Intravenous Infusion of [14C]Bendamustine Hydrochloride in Patients With Relapsed or Refractory Malignancy (Hematologic or Nonhematologic)". Results from this study may indicate a need for dedicated renal and/or hepatic organ impairment studies.
Protocol Submission: May, 2008
Study Start: December, 2008
PK Report Submission: December, 2009
Final Report Submission: March, 2010 - Cephalon has agreed to conduct a study to assess the potential for bendamustine to prolong the QT interval in patients. The QT plan will be submitted prior to initiation for IRT review and concurrence.
Protocol Submission: July, 2008
Study Start: December, 2008
Final Report Submission: June, 2010 - Since bendamustine is a CYP1A2 substrate in vitro, Cephalon has agreed to perform an in vivo drug interaction study of the ability of fluvoxamine (CYP1A2 inhibitor) to alter the pharmacokinetics of a single dose of bendamustine. The necessity to conduct this study will be predicated upon the results from Study 1039.
Protocol Submission: March, 2010
Study Start: September, 2010
PK Report Submission: January, 2012
Final Report Submission: July, 2012 - Since bendamustine is a CYP1A2 substrate in vitro, Cephalon has agreed to perform an in vivo drug interaction study of the ability of smoking (CYP1A2 inducer) to alter the pharmacokinetics of a single dose of bendamustine. The necessity to conduct this study will be predicated upon the results from Study 1039.
Protocol Submission: March, 2010
Study Start: September, 2010
PK Report Submission: July, 2012
Final Report Submission: December, 2012 - Cephalon has agreed to conduct in vitro screens to determine if bendamustine is a pglycoprotein substrate or inhibitor.
Protocol Submission: March, 2008
Study Start: September, 2007
Final Report Submission: June, 2008 - Cephalon has agreed to assess the physico-chemical compatibility of Treanda with the following diluents (not disclosed) as admixtures to reconstituted Treanda.
Protocol submission: April 1, 2008
Study start: May 15, 2008
Final Report: September 1, 2008
Side Effects
Adverse events associated with the use of Treanda may include, but are not limited to, the following:
- Neutropenia
- Pyrexia
- Thrombocytopenia
- Nausea
- Anemia
- Leukopenia
- Vomiting
- Diarrhea
- Fatigue
- Asthenia
Mechanism of Action
Treanda contains bendamustine hydrochloride, an alkylating drug and PARP modulator, as the active ingredient. Bendamustine is a bifunctional mechlorethamine derivative. Mechlorethamine and its derivatives dissociate into electrophilic alkyl groups. These groups form covalent bonds with electron-rich nucleophilic moieties. The bifunctional covalent linkage can lead to cell death via several pathways. However, the exact mechanism of action is unknown.
Literature References
Lissitchkov T, Arnaudov G, Peytchev D, Merkle Kh Phase-I/II study to evaluate dose limiting toxicity, maximum tolerated dose, and tolerability of bendamustine HCl in pre-treated patients with B-chronic lymphocytic leukaemia (Binet stages B and C) requiring therapy. Journal of cancer research and clinical oncology 2006 Feb;132(2):99-104
Bergmann MA, Goebeler ME, Herold M, Emmerich B, Wilhelm M, Ruelfs C, Boening L, Hallek MJ; German CLL Study Group. Efficacy of bendamustine in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase I/II study of the German CLL Study Group. Haematologica 2005 Oct;90(10):1357-64
Schwänen C, Hecker T, Hübinger G, Wölfle M, Rittgen W, Bergmann L, Karakas T In vitro evaluation of bendamustine induced apoptosis in B-chronic lymphocytic leukemia. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 2002 Oct;16(10):2096-105
Kath R, Blumenstengel K, Fricke HJ, Höffken K Bendamustine monotherapy in advanced and refractory chronic lymphocytic leukemia. Journal of cancer research and clinical oncology 2001 Jan;127(1):48-54
Additional Information
For additional information regarding Treanda or chronic lymphocytic leukemia, please visit the Treanda web page.
